The significance of cell structure as reflected in transport systems, sites of hormone action, and multienzyme systems in the integration and regulation of cellular metabolism has been and remains a long-term interest of the principal investigator. As progress has been made in elucidating new mechanisms of hormone action (e.g. second messenger concept) and metabolic regulation (e.g. - role of substrate availability as a rate-limiting parameter for hepatic gluconeogenesis in the intact organism), the applicant has extended the scope of his research activities to encompass additional areas of metabolic and endocrine function both in the laboratory and at the clinical level. During the past six years, our laboratory has carried out extensive studies on the following subjects: 1) Mechanisms and regulation of secretion of insulin and growth hormone, 2) Mechanisms and regulation of insulin synthesis, 3) Cyclic nucleotide metabolism, 4) Regulation of lipoprotein metabolism and 5) Hormone-fuel inter-relationships in the intact organism and the regulation of protein metabolism. The present renewal application requests funds to continue our studies on hormone secretion, insulin synthesis, cyclic nucleotide metabolism, hormone-fuel inter-relationships and the regulation of protein metabolism. Common to all of these studies is the principal investigator's primary objective of defining control mechanisms in precise biochemical and biophysical terms and in applying this information at the clinical level to a definition of the pathophysiologic basis of various metabolic and endocrine disorders.